EP0412941A2 - Phospholipides pour le traitement de la sclérose multiple - Google Patents
Phospholipides pour le traitement de la sclérose multiple Download PDFInfo
- Publication number
- EP0412941A2 EP0412941A2 EP90810594A EP90810594A EP0412941A2 EP 0412941 A2 EP0412941 A2 EP 0412941A2 EP 90810594 A EP90810594 A EP 90810594A EP 90810594 A EP90810594 A EP 90810594A EP 0412941 A2 EP0412941 A2 EP 0412941A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- formula
- compound
- compounds
- group
- use according
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 201000006417 multiple sclerosis Diseases 0.000 title claims abstract description 18
- 150000003904 phospholipids Chemical class 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims description 87
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- -1 alkyl phospholipids Chemical class 0.000 description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 150000004677 hydrates Chemical class 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 6
- 208000024891 symptom Diseases 0.000 description 6
- 239000002246 antineoplastic agent Substances 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 4
- 0 CC1(*OP(*)(OI*)=O)CN(**)*C1 Chemical compound CC1(*OP(*)(OI*)=O)CN(**)*C1 0.000 description 3
- 241000288906 Primates Species 0.000 description 3
- 201000002491 encephalomyelitis Diseases 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 208000032116 Autoimmune Experimental Encephalomyelitis Diseases 0.000 description 2
- 101800000414 Corticotropin Proteins 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 102100027467 Pro-opiomelanocortin Human genes 0.000 description 2
- 206010070834 Sensitisation Diseases 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- IDLFZVILOHSSID-OVLDLUHVSA-N corticotropin Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)NC(=O)[C@@H](N)CO)C1=CC=C(O)C=C1 IDLFZVILOHSSID-OVLDLUHVSA-N 0.000 description 2
- 229960000258 corticotropin Drugs 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 125000005328 phosphinyl group Chemical group [PH2](=O)* 0.000 description 2
- 230000008313 sensitization Effects 0.000 description 2
- 210000000278 spinal cord Anatomy 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 150000003568 thioethers Chemical class 0.000 description 2
- ASWBNKHCZGQVJV-UHFFFAOYSA-N (3-hexadecanoyloxy-2-hydroxypropyl) 2-(trimethylazaniumyl)ethyl phosphate Chemical class CCCCCCCCCCCCCCCC(=O)OCC(O)COP([O-])(=O)OCC[N+](C)(C)C ASWBNKHCZGQVJV-UHFFFAOYSA-N 0.000 description 1
- MHFRGQHAERHWKZ-HHHXNRCGSA-N (R)-edelfosine Chemical compound CCCCCCCCCCCCCCCCCCOC[C@@H](OC)COP([O-])(=O)OCC[N+](C)(C)C MHFRGQHAERHWKZ-HHHXNRCGSA-N 0.000 description 1
- XDUOSORTNCZGHZ-UHFFFAOYSA-N 2-[hydroxy-[(1-octadecoxycarbonylpiperidin-3-yl)methoxy]phosphoryl]oxyethyl-trimethylazanium;hydroxide Chemical compound [OH-].CCCCCCCCCCCCCCCCCCOC(=O)N1CCCC(COP(O)(=O)OCC[N+](C)(C)C)C1 XDUOSORTNCZGHZ-UHFFFAOYSA-N 0.000 description 1
- 239000000275 Adrenocorticotropic Hormone Substances 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 239000000055 Corticotropin-Releasing Hormone Substances 0.000 description 1
- 208000016192 Demyelinating disease Diseases 0.000 description 1
- 206010012305 Demyelination Diseases 0.000 description 1
- 206010033799 Paralysis Diseases 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 208000035286 Spontaneous Remission Diseases 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000002089 crippling effect Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000035622 drinking Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
- A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
Definitions
- the present invention relates to the use of certain heterocyclic, thioether, keto-ester and alkyl phospholipids in the treatment of multiple sclerosis.
- USP 4,778,788 discloses certain lysolecithin analogs useful in treating multiple sclerosis.
- the present invention provides a method of treating multiple sclerosis by administering an effective amount of a compound of formula I: in which n is an integer from 2 to 6; each R3, independently, is methyl or ethyl; and Q is a group of formula II or a group of formula III.
- R is hydrogen or together with R1 forms a group -YCS2CH2CH2- where Y is -O- or -S-; R1 and R2, when R is hydrogen, together form a group where m is 2 to 4 and R4 is n -C(14-20) alkyl or n -C(14-20) alkoxy, or a group where R4 and Y are defined above, or a group where R4 and Y are defined above, or, when R and R1 form a group -YCH2CH2CH2-, R2 is a group -CH2OR5 where R5 is n -C(14-20) alkyl.
- R6 is hydrogen and R7 is n -C(12-18) alkyl, or R6 is -CH2SR5 and R7 is -CH2OR3, or R6 is -CH2OR5 and R7 is -OCOCH2COCH3; where R3 and R5 are defined above.
- n is n′ where n′ is 2,3 or 4, more preferably 2.
- R3 is preferably methyl.
- R4 is preferably R4′ where R4′ is n -C(14-18)alkyl or n -C(14-18)alkoxy; more preferably it is n -C(16-18)alkoxy, particularly n -C18H37O-.
- R5 is preferably R5′ where R5′ is n -C(14-18)alkyl, particularly n -C16 or C18 alkyl.
- one class of compounds found useful in the practice of this invention is the heterocyclic phospholipids of formula IV: where X is ( ⁇ CH2) ⁇ , where m is 2 to 4; -CH2CH2O- or -CH2CH2S-: and n, R3 and R4 are as defined above; and the corresponding hydrates thereof.
- the preferred compounds of subclass IVa are the compounds of formula IVa′: where n′, R4′ and X′ are as defined above, and the corresponding hydrates thereof.
- the most preferred compounds of subclass IVa are 2-[[hydroxy[(1-octadecyloxycarbonyl-3-piperidinyl)-methoxy]phosphinyl]oxy]-N,N,N-trimethylethanaminium hydroxide inner salt-4-oxide having the formula ( ⁇ )-2-[hydroxy[(1-octadecyloxycarbonyl-3-pyrrolidinyl)-methoxy]phosphinyl]oxy]-N,N,N-trimethylethanaminium hydroxide inner salt-4-oxide, dihydrate having the formula and ( ⁇ )-2-[[hexahydro-1-octadecyloxycarbonyl-1H-azepin-3-yl)-methoxy]hydroxy phosphinyl]oxy]-N,N,N,trimethylethanaminium hydroxide inner salt-4-oxide, 1.5 hydrate having the formula
- n, R3, R4 and Y are as defined above; and the corresponding hydrates thereof.
- the preferred compounds of subclass IVb are the compounds of formula IVb′: where Y, R4′ and n′ are as defined above; and the corresponding hydrates thereof.
- the most preferred compounds of subclass IVb are ( ⁇ )-2-[hydroxy[(4-octadecyloxycarbonyl-2-morpholinyl)-methoxy]phosphinyl]oxy]-N,N,N-trimethylethanaminium hydroxide inner salt-4-oxide, trihydrate having the formula and ( ⁇ )-2-[hydroxy[(tetrahydro-4-octadecyloxycarbonyl-2H-1,4-thiazin-2-yl)methoxy]phosphinyl]oxy]-N,N,N-trimethylethanaminium hydroxide inner salt-4-oxide, monohydrate having the formula
- a further class of compounds of formula I in which Q is a group of formula II found useful in the practice of this invention is the heterocyclic phospholipids of formula V: where Y, R3, R5, and n are as defined above.
- the preferred compounds of formula V are compounds of formula V′ where n′, Y and R5′, are as defined above.
- the most preferred compound of formula V is 2-1[[2-octadecyloxymethyltetrahydro-2-furanylmethoxy)-hydroxy-phosphinyloxy]-N,N,N,-trimethylethanaminium hydroxide inner salt-4-oxide having the formula
- a class of compounds of formula I in which Q is a group of formula III found useful in the practice of this invention is the thioether phospholipids of formula VI: where n, R3 and R5 are as defined above.
- the preferred compounds of formula VI are compounds of formula VI′: where n′ and R5′ are as defined above.
- the most preferred compound of formula VI is 3-hexadecylmercapto-2-methoxymethylpropyl-2′-trimethylammonioethyl phosphate having the formula
- keto-ester phospholipids of formula VII Another class of compounds of formula I in which Q is a group of formula III found useful in the practice of this invention is the keto-ester phospholipids of formula VII: where R5, R3 and n are as defined above.
- the preferred compounds of formula VII are compounds of formula VII′: where R5′ and n′ are as defined above.
- the most preferred compound of formula VII is 3,5,9-trioxa-4-phosphaheptacosan-1-aminium,7-(1,3-dioxo-butoxy)-N,N,N-trimethyl, hydroxide inner salt, 4-oxide having the formula
- Yet another class of compounds of formula I in which Q is a group of formula III found useful in the practice of this invention is the alkyl phospholipids of formula VIII: where R7 and n are as defined above.
- the preferred compounds of formula VIII are compounds of formula VIII′: where R7′ is n -C( 12-16) alkyl and n is as defined above.
- the most preferred compound of formula VIII is the compound hexadecyl-2-trimethylammonioethylphosphate having the formula:
- the compounds of formulae IV, V, VI and VII contain an asymmetric carbon atom. It should be understood, therefore, that the compounds may exist in racemic or enantiomeric form, and all forms are included within the practice of this invention. Enantiomeric forms may be recovered in conventional manner, e.g., by resolution of end or intermediate products or by employing optically active starting materials.
- EAE Experimentally Induced Allergic Encephalomyelitis
- mice Male Wistar rats are injected in the hind paws with a mixture of bovine spinal cord and complete Freund's adjuvant. Symptoms of the disease (paralysis of the tail and both hind legs) usually develop within 16 days. The number of diseased animals as well as the time of onset of the disease are recorded.
- Test is carried out analogously to that described above with the exception that the administration of the test compound commences on day 8 to day 9 after sensitization (i.e., immediately prior to appearance of disease symptoms) at dosages of from 5 to 50 mg/kg/day either daily or every second day and continuing for 2 weeks. During the testing period, the animals are examined daily for symptoms of the disease and scored as in the above test method.
- a compound of formula I particularly a compound of formula IV or a corresponding hydrate, V, VI, VII or VIII to be employed in treating multiple sclerosis depends upon several factors including the host, the nature and the severity of the condition being treated, the mode of administration and the particular compound employed. However, in general, satisfactory inhibition of the symptoms of multiple sclerosis is achieved when a compound of formula I, is administered orally at a daily dosage of 0.5-30 mg/kg body weight, preferably 1-20 mg/kg or, for most larger primates, at a total daily dosage of 35-600 mg. A preferred total daily dosage for most larger primates is 150 to 300 mg.
- a small dosage is administered initially and the dosage is gradually increased until the optimal dosage for the host under treatment is determined.
- the upper limit of dosage is that imposed by side effects, and can be determined by trials for the host being treated, including humans.
- a preferred total daily dosage for most larger primates is 150 to 300 mg.
- the dosage regimen can be decreased to between 150 and 300 mg of a compound of formula I, every second day.
- the compounds of formula I may be combined with one or more pharmaceutically acceptable carriers and, optionally, one or more conventional pharmaceutical adjuvants and administered orally in the form of tablets, dispersible powders, granules, capsules, elixirs, suspensions and the like.
- the compositions may be prepared by conventional means.
- the compounds may be dissolved in a small quantity of a suitable solvent, for example ethanol, and diluted with milk for drinking.
- the compounds of formula I may be formulated into such pharmaceutical compositions containing an amount of the active substance that is effective in treating multiple sclerosis, such compositions in unit dosage form and such compositions comprising a solid pharmaceutically acceptable carrier.
- Tablets and capsules containing the ingredients indicated below may be prepared by conventional techniques and are useful in treating multiple sclerosis when administered once a day.
- the present invention additionally provides:
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Fats And Perfumes (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US39218789A | 1989-08-10 | 1989-08-10 | |
US392187 | 1989-08-10 | ||
US42332389A | 1989-10-18 | 1989-10-18 | |
US423323 | 1989-10-18 | ||
US48957890A | 1990-03-07 | 1990-03-07 | |
US489578 | 1990-03-07 |
Publications (3)
Publication Number | Publication Date |
---|---|
EP0412941A2 true EP0412941A2 (fr) | 1991-02-13 |
EP0412941A3 EP0412941A3 (en) | 1992-01-02 |
EP0412941B1 EP0412941B1 (fr) | 1996-05-15 |
Family
ID=27410008
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP90810594A Expired - Lifetime EP0412941B1 (fr) | 1989-08-10 | 1990-08-07 | Phospholipides pour le traitement de la sclérose multiple |
Country Status (9)
Country | Link |
---|---|
EP (1) | EP0412941B1 (fr) |
JP (1) | JPH075468B2 (fr) |
KR (1) | KR910004196A (fr) |
AT (1) | ATE137973T1 (fr) |
AU (1) | AU629967B2 (fr) |
DE (1) | DE69026991T2 (fr) |
DK (1) | DK0412941T3 (fr) |
ES (1) | ES2086395T3 (fr) |
GR (1) | GR3020597T3 (fr) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR101523312B1 (ko) * | 2013-12-03 | 2015-05-27 | 한국원자력연구원 | 백금족 원소를 포함하는 방사성 요오드 포집 용액 및 이를 이용한 방사성 요오드의 포집 방법 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1987001257A2 (fr) * | 1985-08-28 | 1987-03-12 | Max-Planck-Gesellschaft Zur Förderung Der Wissensc | Agent contre la sclerose multiple |
EP0225608A2 (fr) * | 1985-12-04 | 1987-06-16 | Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. | Médicament |
US4749696A (en) * | 1985-08-30 | 1988-06-07 | Sandoz Pharm. Corp. | Hydroxy-[1-substituted carbonyl-2-(or 3-) piperidinyl methoxy]phosphinyloxy]-N,N,N-trialkylalkaneaminium hydroxide inner salt oxides having antitumor activity |
-
1990
- 1990-08-07 AT AT90810594T patent/ATE137973T1/de active
- 1990-08-07 DE DE69026991T patent/DE69026991T2/de not_active Expired - Fee Related
- 1990-08-07 EP EP90810594A patent/EP0412941B1/fr not_active Expired - Lifetime
- 1990-08-07 ES ES90810594T patent/ES2086395T3/es not_active Expired - Lifetime
- 1990-08-07 DK DK90810594.3T patent/DK0412941T3/da active
- 1990-08-08 JP JP2208296A patent/JPH075468B2/ja not_active Expired - Lifetime
- 1990-08-08 AU AU60290/90A patent/AU629967B2/en not_active Ceased
- 1990-08-09 KR KR1019900012223A patent/KR910004196A/ko not_active Application Discontinuation
-
1996
- 1996-07-23 GR GR960401956T patent/GR3020597T3/el unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1987001257A2 (fr) * | 1985-08-28 | 1987-03-12 | Max-Planck-Gesellschaft Zur Förderung Der Wissensc | Agent contre la sclerose multiple |
US4749696A (en) * | 1985-08-30 | 1988-06-07 | Sandoz Pharm. Corp. | Hydroxy-[1-substituted carbonyl-2-(or 3-) piperidinyl methoxy]phosphinyloxy]-N,N,N-trialkylalkaneaminium hydroxide inner salt oxides having antitumor activity |
EP0225608A2 (fr) * | 1985-12-04 | 1987-06-16 | Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. | Médicament |
Non-Patent Citations (2)
Title |
---|
BIOCHIMICA ET BIOPHYSICA ACTA, vol. 820, no. 2, 1985, pages 319-323, Elsevier Science Publishers B.V. (Biomedical Division); W.K. SUREWICZ et al.: "Aliphatic aldehydes promote myelin basic protein-induced fusion of phospholipid vesicles" * |
JOURNAL OF NEUROLOGY, vol. 207, no. 4, 1974, pages 319-326, Springer-Verlag; H. WOELK et al.: "Zur Aktivit{t der Phospholipase A2 gegen}ber verschiedenen 1-Alk-1'-enyl-2-acyl- und 1-Alkyl-2-acyl-Verbindungen w{hrend der multiplen Sklerose" * |
Also Published As
Publication number | Publication date |
---|---|
DE69026991D1 (de) | 1996-06-20 |
GR3020597T3 (en) | 1996-10-31 |
AU629967B2 (en) | 1992-10-15 |
JPH0377826A (ja) | 1991-04-03 |
AU6029090A (en) | 1991-02-14 |
JPH075468B2 (ja) | 1995-01-25 |
KR910004196A (ko) | 1991-03-28 |
DE69026991T2 (de) | 1997-01-16 |
ES2086395T3 (es) | 1996-07-01 |
DK0412941T3 (da) | 1996-06-24 |
EP0412941A3 (en) | 1992-01-02 |
ATE137973T1 (de) | 1996-06-15 |
EP0412941B1 (fr) | 1996-05-15 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP1009397A2 (fr) | Chlorure de n,n-bis (phenylcarbamoylmethyl) dimethylammonium et ses derives, servant au traitement de la douleur | |
EP0425909A2 (fr) | Méthode pour restaurer l'activité vasorelaxante des artères coronaires, amoindrie par l'athérosclérose ou l'hypercholestérolémie, en utilisant un inhibiteur de l'ACE | |
JP2020520374A (ja) | 関節リウマチの治療用組成物および治療方法 | |
CZ20012231A3 (cs) | Použití bisfosfonátů k profylaxi a k ošetřování infekčních procesů | |
EP0368343B1 (fr) | Composition modifiant la dysmnésie | |
EP0381075A2 (fr) | Méthode pour traiter l'asservissement aux drogues, en utilisant un inhibiteur de l'enzyme de conversion de l'angiotensine | |
EP0412941A2 (fr) | Phospholipides pour le traitement de la sclérose multiple | |
JP2001527551A (ja) | Mtpインヒビターと脂溶性ビタミンの組合せおよび該組合せを用いる血清脂質レベルの降下法 | |
US5064816A (en) | Heterocyclic phospholipids useful in treating multiple sclerosis | |
US6903080B2 (en) | Disease treatment with novel phospholipid derivatives | |
US5182271A (en) | Thioether, keto-ester and alkyl phospholipids useful in treating multiple sclerosis | |
CA2022873A1 (fr) | Composes pharmaceutiques pour le traitement de la sclerose en plaques | |
US5082846A (en) | Use of the R-(+)-isomer of 2-methoxy-3-octadecyloxy-propanol-(1)-phosphoric acid, monocholine ester in treating multiple sclerosis | |
EP0381074A2 (fr) | Méthode pour suivre un régime de façon plus aisée, en utilisant un inhibiteur de l'enzyme de conversion de l'angiotensine | |
EP0382842B1 (fr) | Nootropique | |
CA1209047A (fr) | Compose therapeutique contenant un analogue du piracetam | |
CS567090A3 (en) | Therapeutical agents | |
EP0222578A2 (fr) | Utilisation d'analogues cycliques de la somatostatine pour le traitement des maladies d'hypersensitivité immédiate | |
US3714365A (en) | Reducing abnormally high plasma lipid levels in mammals with phenols | |
US4877784A (en) | Histidylprolineamide derivatives | |
US5141933A (en) | Treatment for hyperglycaemia | |
US4988720A (en) | Novel treatment of hyperglycaemia | |
JPH04208223A (ja) | 肝臓疾患治療剤 | |
EP0609335A1 (fr) | Procedes de traitement de l'hyperlipidemie consistant a utiliser des azaspiranes | |
KR920003580B1 (ko) | 동맥경화증 예방 및 치료제 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 19900809 |
|
AK | Designated contracting states |
Kind code of ref document: A2 Designated state(s): AT BE CH DE DK ES FR GB GR IT LI LU NL SE |
|
PUAL | Search report despatched |
Free format text: ORIGINAL CODE: 0009013 |
|
AK | Designated contracting states |
Kind code of ref document: A3 Designated state(s): AT BE CH DE DK ES FR GB GR IT LI LU NL SE |
|
17Q | First examination report despatched |
Effective date: 19940714 |
|
GRAH | Despatch of communication of intention to grant a patent |
Free format text: ORIGINAL CODE: EPIDOS IGRA |
|
GRAA | (expected) grant |
Free format text: ORIGINAL CODE: 0009210 |
|
AK | Designated contracting states |
Kind code of ref document: B1 Designated state(s): AT BE CH DE DK ES FR GB GR IT LI LU NL SE |
|
REF | Corresponds to: |
Ref document number: 137973 Country of ref document: AT Date of ref document: 19960615 Kind code of ref document: T |
|
REF | Corresponds to: |
Ref document number: 69026991 Country of ref document: DE Date of ref document: 19960620 |
|
REG | Reference to a national code |
Ref country code: DK Ref legal event code: T3 |
|
REG | Reference to a national code |
Ref country code: ES Ref legal event code: FG2A Ref document number: 2086395 Country of ref document: ES Kind code of ref document: T3 |
|
ITF | It: translation for a ep patent filed | ||
ET | Fr: translation filed | ||
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: NL Payment date: 19960926 Year of fee payment: 8 |
|
REG | Reference to a national code |
Ref country code: GR Ref legal event code: FG4A Free format text: 3020597 |
|
PLBE | No opposition filed within time limit |
Free format text: ORIGINAL CODE: 0009261 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT |
|
26N | No opposition filed | ||
REG | Reference to a national code |
Ref country code: CH Ref legal event code: PFA Free format text: SANDOZ LTD. TRANSFER- NOVARTIS AG |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: SE Payment date: 19970602 Year of fee payment: 8 Ref country code: FR Payment date: 19970602 Year of fee payment: 8 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: BE Payment date: 19970604 Year of fee payment: 8 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: DE Payment date: 19970605 Year of fee payment: 8 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: DK Payment date: 19970619 Year of fee payment: 8 |
|
REG | Reference to a national code |
Ref country code: GB Ref legal event code: 732E |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: GB Payment date: 19970630 Year of fee payment: 8 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: CH Payment date: 19970707 Year of fee payment: 8 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: AT Payment date: 19970807 Year of fee payment: 8 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: ES Payment date: 19970808 Year of fee payment: 8 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: LU Payment date: 19970813 Year of fee payment: 8 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: GR Payment date: 19970826 Year of fee payment: 8 |
|
NLS | Nl: assignments of ep-patents |
Owner name: NOVARTIS AG |
|
REG | Reference to a national code |
Ref country code: FR Ref legal event code: TP |
|
REG | Reference to a national code |
Ref country code: ES Ref legal event code: PC2A |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: LU Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 19980807 Ref country code: GB Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 19980807 Ref country code: AT Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 19980807 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: SE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 19980808 Ref country code: ES Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 19980808 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: LI Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 19980831 Ref country code: GR Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 19980831 Ref country code: DK Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 19980831 Ref country code: CH Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 19980831 Ref country code: BE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 19980831 |
|
BERE | Be: lapsed |
Owner name: NOVARTIS A.G. Effective date: 19980831 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: NL Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 19990301 |
|
GBPC | Gb: european patent ceased through non-payment of renewal fee |
Effective date: 19980807 |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: PL |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: FR Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 19990430 |
|
EUG | Se: european patent has lapsed |
Ref document number: 90810594.3 |
|
NLV4 | Nl: lapsed or anulled due to non-payment of the annual fee |
Effective date: 19990301 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: DE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 19990601 |
|
REG | Reference to a national code |
Ref country code: FR Ref legal event code: ST |
|
REG | Reference to a national code |
Ref country code: DK Ref legal event code: EBP |
|
REG | Reference to a national code |
Ref country code: ES Ref legal event code: FD2A Effective date: 19990910 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: IT Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES;WARNING: LAPSES OF ITALIAN PATENTS WITH EFFECTIVE DATE BEFORE 2007 MAY HAVE OCCURRED AT ANY TIME BEFORE 2007. THE CORRECT EFFECTIVE DATE MAY BE DIFFERENT FROM THE ONE RECORDED. Effective date: 20050807 |